Infertility resident survival guide

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:  Sanjana Nethagani, M.B.B.S.[2]

Synonyms and keywords: Approach to Infertility, Approach to subfertility, Approach to impotence

Infertility Resident Survival Guide Microchapters

Overview
Causes
Diagnosis
Treatment
Dos
Don'ts

## Overview

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Infertility is defined as a failure to conceive after one or more years of unprotected intercourse. Infertility is divided broadly into primary and secondary infertility where primary infertility is failure to conceive and secondary infertility is failure to conceive after a previous pregnancy. Multiple factors play a role in conception and infertility such as healthy spermatozoa, regular ovulation, patent fallopian tubes, normal uterine cavity etc.

## Causes

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Common causes of female infertility are listed below.

### Genetic causes

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* Turner's syndrome[1]
* Mayer-Rokitansky-Kuster-Hauser syndrome
* Kallmann syndrome
* Primary ciliary dyskinesia

### Endocrine causes

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* Hypothyroidism[2]
* Hypopituitarism
* Hyperprolactinemia
* Polycystic ovarian syndrome
* Congenital adrenal hyperplasia
* Hypogonadotropic hypergonadism

### Ovarian causes

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* Anovulation
* Luteal phase defect
* Luteinised unruptured follicle

### Tubal causes

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* Pelvic inflammatory disease causing adhesions and endosalpingeal damage
* Previous tubal surgery
* Tubal endometriosis

### Uterine causes

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* Polyps[3]
* Fibroids
* Endometriosis[4]
* Congenital uterine anomalies such as septate uterus
* Uterine hypoplasia

### Cervical factors

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* Congenital elongation of cervix
* Uterine prolapse
* Cauterization of cervix

### Vaginal factors

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* Vaginal atresia
* Transverse vaginal septum
* Septate vagina
* Vaginitis

### Miscellaneous factors

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* Advanced age
* Anxiety
* Dyspareunia
* Contraceptive use

## Diagnosis

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Shown below is an algorithm summarizing the diagnosis of female infertility according to the American College of Gynecology and Obstetricians 2019 Committee Opinion on Infertility Workup for the Woman's Health Specialist and Evaluation, Global Infertility Guidelines published in 1992 by the WHO, updated in 2012, and The Treatment of Infertility Guidelines by the American Family Physician. [5][6][7][8]

Abbreviations: STD \- Sexually transmitted disease, FSH \- Follicle stimulating hormone, LH \- Luteinizing hormone, TSH \- Thyroid stimulating hormone, CT \- Computed tomography, MRI \- Magnetic resonance imaging, IVF \- In vitro fertilization

| Couple with infertility|

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Detailed history including
❑ Any history of abdominal or pelvic surgery?
❑ Menstrual history
❑ History of contraceptive use
❑ Obstetric history
❑ Any history of diethylstilbestrol exposure
❑ Frequency of intercourse
❑ Any history of STDs in either partner
❑ History of acne, hirsutism or recent weight changes

Physical examination
❑ Height, weight and BMI
Head and neck examination for
❑ Exophthalmos
❑ Webbed neck
❑ Epicanthal fold
❑ Presence of any neck swellings
❑ Breast examination for any swellings or nipple discharge
❑ Any swellings in the abdomen
Thorough gynecological exam including
❑ Distribution of pubic hair
❑ If there is presence of any clitoral enlargement
❑ Signs of STDs
Bimanual exam might detect the presence of
❑ Uterine fibroids
❑ Cervical motion tenderness
❑ Presence of vaginal septae

Initial investigations
❑ Urine examination
❑ Complete blood count
❑ Fasting and post prandial blood sugar estimation
❑ Semen analysis
❑ Hysterosalpingography

| Normal semen analysis

Ovarian causes|

| Endometrial causes|

| Cervical causes|

| Fallopian tube causes

Methods to detect ovulation
❑ Basal body temperature measurement throughout cycle
❑ Vaginal cytology
❑ Cervical mucus study
❑ Serum progesterone
❑ Serum Luteinizing hormone
❑ Serum estradiol
❑ Urine Luteinizing hormone level
❑ Transvaginal ultrasound

| Endometrial biopsy on day 21-23|

| Cervical mucus study/ Sperm cervical mucus contact test|

❑ Hysterosalpingography
❑ Laparoscopy

Anovulatory cycle|

| Ovulatory cycle|

| Progressive motile sperm seen|

| Sperm antibodies

Investigate the following
❑ Serum FSH
❑ Serum LH
❑ Serum Prolactin
❑ TSH level
❑ If hirsutism is present check testosterone levels and 17-Hydroxyprogesterone levels
❑ If FSH and LH levels are in the low-normal range, but with high prolactin, consider CT or MRI of the head

| If age is >30 years, work up with all other investigations including day 3 FSH|

| Occasionally, IgG, IgA or IgM antibodies are found against sperm. Treating these anti-sperm antibodies have not shown an improved outcome in pregnancies. Treatment is along the lines of IVF

| Non secretory endometrium|

| Secretory endometrium

| Luteal phase defect

| Confirmed by basal body temperature or repeat endometrial biopsy and serum progesterone estimated on 8th day

## Treatment

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Shown below is an algorithm summarizing the treatment of infertility. [9][4]

Abbreviations: hMG\- Human menopausal gonadotropin, FSH\- Follicle stimulating hormone, CAH\- Congenital adrenal hyperplasia, ART\- Assisted reproductive technology, PCOS\- Polycystic ovarian syndrome

| Thorough history and initial investigations

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| Ovulatory causes|

| Tubal causes|

| Cervical causes|

| Endocrinopathies|

| Uterine causes|

| Other causes

Anovulation
Induction of ovulation can be done by
❑ Clomiphene citrate
❑ hMG
❑ Purified/recombinant FSH
❑ Gonadotropin-releasing hormone and its analogues
Assisted reproductive techniques such as
❑ In vitro fertilization
❑ cryopreservation of gametes or fertilized embryos
❑ Intracytoplasmic sperm injection
❑ Egg donation via donors

Correction of biochemical abnormalities
❑ Hyperinsulinemia or insulin resistance - Metformin
❑ Hyperprolactinemia \- Bromocriptine

❑ Cervicitis is treated with doxycycline or other antibiotics
❑ Quality of cervical mucus is improved with oral estrogen

❑Uterine fibroids are treated by myomectomy
❑ Uterine septum is corrected by a metroplasty
❑ Polyps are treated by polypectomy
❑ Hysteroscopic adhesiolysis in cases of synechiae

❑ Uncontrolled diabetes must be treated before exploring other options
❑ Hyperthyroidism and Grave's disease causing infertility can be corrected with antithyroid drugs
❑ Hypothyroidism induced infertility is corrected when euthyroid state is achieved
❑ CAH causes infertility which can be corrected with clomiphene and other ovulation induction techniques
ARTs are used when ovulation stimulation fails
❑ Treating infertility in PCOS is a multidisciplinary approach and involves
Glycemic control with metformin
Reduction of weight when applicable
Oral contraceptive pills
Ovulation induction with clomiphene
Antiandrogens such as flutamide and spironolactone for acne and hirsutism
❑ Hyperprolactinemia induced infertility is treated with dopamine agonists such as cabergoline

❑Pelvic inflammatory disease \- Identify the infecting agent and start appropriate antibiotic therapy
Treat sexual partner for any STIs
❑ Adhesions\- surgical correction
❑ In vitro fertilization

Unexplained infertility is a diagnosis of exclusion after semen analysis and all other tests are normal
Treatment can include the following
❑ Ovulation induction with clomiphene
❑ Intrauterine insemination
❑ Invitro fertilization

## Dos

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* Prompt and early treatment of PID must be done to prevent infertility. [10]
* Effective counseling about male and female components of infertility.
* Educate the patient about toxic effects of nicotine, marijuana, and other drugs and their impact on fertility if the patient is a known user. [11]
* Risk of ectopic pregnancy, multiple gestations and ovarian hyperstimulation syndrome must be explained.[12]

## Don'ts

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* Don't ignore the risk of ovarian hyperstimulation syndrome in patients undergoing ovulation induction, particularly in patients who have had PCOS. [13]
* Don't pursue assisted reproductive technology without first correcting underlying endocrinopathy when present.

## References

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1. ↑ Hovatta O (1999). "Pregnancies in women with Turner's syndrome". Ann Med. 31 (2): 106–10. PMID 10344582.
2. ↑ Luciano AA, Lanzone A, Goverde AJ (2013). "Management of female infertility from hormonal causes". Int J Gynaecol Obstet. 123 Suppl 2: S9–17. doi:10.1016/j.ijgo.2013.09.007. PMID 24139473.CS1 maint: Multiple names: authors list (link)
3. ↑ Abrao MS, Muzii L, Marana R (2013). "Anatomical causes of female infertility and their management". Int J Gynaecol Obstet. 123 Suppl 2: S18–24. doi:10.1016/j.ijgo.2013.09.008. PMID 24119894.CS1 maint: Multiple names: authors list (link)
4. ↑ 4.0 4.1 Tanbo T, Fedorcsak P (2017). "Endometriosis-associated infertility: aspects of pathophysiological mechanisms and treatment options". Acta Obstet Gynecol Scand. 96 (6): 659–667. doi:10.1111/aogs.13082. PMID 27998009.
5. ↑ Smith S, Pfeifer SM, Collins JA (2003). "Diagnosis and management of female infertility". JAMA. 290 (13): 1767–70. doi:10.1001/jama.290.13.1767. PMID 14519712.CS1 maint: Multiple names: authors list (link)
6. ↑ "Infertility Workup for the Women's Health Specialist: ACOG Committee Opinion, Number 781". Obstet Gynecol. 133 (6): e377–e384. 2019. doi:10.1097/AOG.0000000000003271. PMID 31135764.
7. ↑ Lindsay TJ, Vitrikas KR (2015). "Evaluation and treatment of infertility". Am Fam Physician. 91 (5): 308–14. PMID 25822387.
8. ↑ "Recent advances in medically assisted conception. Report of a WHO Scientific Group". World Health Organ Tech Rep Ser. 820: 1–111. 1992. PMID 1642014.
9. ↑ Macer ML, Taylor HS (2012). "Endometriosis and infertility: a review of the pathogenesis and treatment of endometriosis-associated infertility". Obstet Gynecol Clin North Am. 39 (4): 535–49. doi:10.1016/j.ogc.2012.10.002. PMC 3538128. PMID 23182559.
10. ↑ Haggerty CL, Ness RB (2006). "Epidemiology, pathogenesis and treatment of pelvic inflammatory disease". Expert Rev Anti Infect Ther. 4 (2): 235–47. doi:10.1586/14787210.4.2.235. PMID 16597205.
11. ↑ Messi E, Pimpinelli F, Andrè V, Rigobello C, Gotti C, Maggi R (2018). "The alpha-7 nicotinic acetylcholine receptor is involved in a direct inhibitory effect of nicotine on GnRH release: In vitro studies". Mol Cell Endocrinol. 460: 209–218. doi:10.1016/j.mce.2017.07.025. PMID 28754351.CS1 maint: Multiple names: authors list (link)
12. ↑ Shah JS, Roman T, Viteri OA, Haidar ZA, Ontiveros A, Sibai BM (2018). "The Relationship of Assisted Reproductive Technology on Perinatal Outcomes in Triplet Gestations". Am J Perinatol. 35 (14): 1388–1393. doi:10.1055/s-0038-1660457. PMID 29883983.CS1 maint: Multiple names: authors list (link)
13. ↑ Nelson SM (2017). "Prevention and management of ovarian hyperstimulation syndrome". Thromb Res. 151 Suppl 1: S61–S64. doi:10.1016/S0049-3848(17)30070-1. PMID 28262238.